1R21AI081060-01A1 Koelle, David M. HSV-1 is a significant human pathogen, causing serious infections of the cornea, retina, brain parenchyma, and facial and oral tissues, and also causing perinatal morbidity and mortality. There is no licensed vaccine for HSV-1. The locus of chronic HSV-1 infection is within neurons in sensory ganglia, particularly the trigeminal ganglia (TG) that enervate that face, cornea, and meninges. Animal models of HSV-1 infection have recently proven that the TG is an immunocompetent organ with regard to the presence of ganglia-resident, HSV-1-specific CD8 and CD4 T-cells, and that these cells are functionally important in explant and transplant systems. To study chronic phase TG HSV-1 immunology in the natural host that HSV-1 has been co-evolving with for millions of years, the present application focuses on the TG immune response to HSV-1 in tissue from anonymous human cadavers. The long term goals of the HSV-1 research program are the rational design of an HSV-1 subunit vaccine and an understanding of antigen processing and presentation to HSV-1-specific T-cells in human TG. This grant represents the beginning of a planned sustained focus on HSV-1 immunology. The first Aim is to determine which HSV-1 epitopes and antigens are recognized by HSV-1-specific CD8 T-cells in human HSV-1-infected trigeminal ganglia. We will use a virtual HSV-1 ORFeome and artificial antigen presenting cells to dissect the HSV-1-specific CD8 T-cell response in TG tissues. The second Aim is to determine which HSV-1 epitopes and antigens are recognized by HSV-1-specific CD4 T-cells in human TG tissues. Antigens that contain multiple epitopes within-donor, that are recognized by T-cells from multiple donors, and are recognized by both CD4 and CD8 T-cells, if these are detected, will be rational candidates for HSV-1 subunit or vectored vaccines.